1. Field of the Invention
This invention relates to lysosome liberation inhibitors and histamine release inhibitors, which comprise certain cembrane-type diterpene compounds as active ingredients.
2. Description of the Prior Art
Cembrane-type diterpene compounds are found in coelenterates belonging to the orders Gorgonacea and Alcyonacea. Recently, some of them have been found to exhibit an anti-tumor activity: see, for instance, B. Tursch et al., Tetrahedron, 31, 129 (1975); and A. J. Weinheimer et al., Tetrahedron Letters, 2923 (1977).
Under these circumstances, Hirayama et al. have studied a coelenterate "Ohumikinoko" (Sarcophyton glaucum) belonging to the order Alcyonacea and finally discovered new cembrane-type diterpene compounds having an anti-solid tumor activity: see, for instance, Japanese Patent Application Laying-open (KOKAI) No. 61318/81.
Although such anti-solid tumor activities of these compounds have been reported, there has been no report on their anti-inflammatory activities or their effects on inflammatory cells such as polymorphonuclear leukocytes and mast cells.
Recently, it has been said that there may be some doubts in the prostaglandin hypothesis which has importantly been utilized to elucidate the etiology of chronic inflammation. Instead, a new, active oxygen hypothesis has been proposed. Thus, polymorphonuclear leukocytes and macrophages possess a phagocytic activity and are said to digest intruding foreign materials and to kill invading bacteria. Reactions of polymorphonuclear leukocytes or macrophages with bacteria or antigen-antibody complexes will produce active oxygen 0.sub.2.sup..- and/or hydroxyl radical OH, thereby directly causing damage to tissues and/or resulting in liberation of lysosomal enzymes.
There have been many reports suggesting a certain intimate relationship between inflammation and lysosomal enzymes liberated from leukocytes.
At present, chronic inflammation in which lysosomes may be involved may include rheumatoid arthritis, nephritis, pseudogout etc. In these diseases, pathological liberation of lysosomes will cause inflammatory conditions accompanied with pain. Thus, it is considered that chronic inflammation may be caused by persistent liberation of lysosomes into extracellular environment.
If such liberation of lysosomes could be inhibited, the conversion of inflammatory conditions into chronic ones would be delayed and/or prevented.
It has been known that mast cells are basophilic granulocytes which are widely found in various connective tissues and show metachromasia upon staining with basic dyes. It has also been known that the mast cells release mediators of allergic reactions such as histamine and leukotrienes.
Formerly, connective tissues were recognized merely as possessing supporting function. However, the connective tissues may now have been considered to control various cellular activities, e.g., cellular nourishment, elimination of cellular metabolites, preservation of cellular environment, protection of cell groups from extraneous invasion by serving as inflammatory sites, or the like.
In the course of the recent progress in cell biology and biochemistry, mast cells per se have become again recognized as very important cells responsible for a variety of physiological activities: "TAISHA" (Metabolism), Vol. 13, No. 5, "Special Issue on Mast Cells", Nakayama Shoten, Tokyo, Japan.
In recent years, for instance, new findings as to the etiology of ulcerative colitis have been accumulated and, as a result, destruction of the defense mechanism against invasion of antigens such as bacteria from the intestinal tract and establishment of autoimmunity to the colic mucosa are now considered to be the pathogenesis of persistent inflammation in the colic mucosa, which is a main symptom of this disease.
Both immediate-type and delayed-type allergies are involved in this ulcerative colitis. In its acute stage, the establishment of the immediate-type allergy in the colic mucosa will cause the symptoms. Thus, elevated plasma histamine levels, increases of eosinophils in the colic mucosa, and decreases of mast cells may be observed at this stage. The immediate-type allergy will cause induction of vasoactive substances and disturbance of intestinal microcirculation and, correspondingly, various acute sumptoms are developed due to hyperpermeability of the intestinal mucosa and enhanced myospasm.
It has been reported that cromoglycate, which inhibits degranulation of mast cells, namely, which is an inhibitor of histamine release, may be effective in the ulcerative colitis. Thus, compounds having a potent inhibitory activity against release of histamine from mast cells may be expected to be very effective for the treatment of ulcerative colitis.
It has recently become recognized that histamine plays an important role not only as a mediator of the initial stage in acute inflammation but also as an agent controlling conversion of inflammation into chronic conditions as well. For instance, it is said that histamine receptors are present in fibroblasts and collagen production in the cells is enhanced by histamine. In addition, the fact that mast cells will increase in fibrous tissues with inflammation has been established.
Accordingly, inhibition of histamine release from mast cells would suppress, in an indirect manner, acceleration of fibrosis, i.e., enhancement of collagen production, in tissues under chronic inflammatory conditions. For example, such inhibition may be useful in the treatment of diseases accompanied with abnormal fibrous proliferation, pulmonary fibrosis, postoperative cheloids, abnormal fibrous proliferation due to trauma.